CNR1
GeneName
CNR1
Summary
CNR1, also known as CB1 or CBR, is a 53kDa G protein-coupled receptor primarily expressed in the central nervous system and peripheral tissues. It is localised to various cellular components, including the plasma membrane, presynaptic membrane, and membrane rafts. CNR1 plays a critical role in cannabinoid signalling pathways, mediating the effects of endocannabinoids on neuronal communication. Its functions include regulation of presynaptic calcium ion concentrations and involvement in metabolic processes, such as glucose homeostasis. CNR1 is also implicated in axonal fasciculation and retrograde trans-synaptic signalling, highlighting its importance in synaptic plasticity and neural development.
Importance
CNR1 is relevant to: - The study of cannabinoid pharmacology and its therapeutic potential in pain management and neurological disorders - Understanding the mechanisms of addiction and the effects of cannabinoids on the brain - Research into metabolic regulation and obesity due to its role in glucose homeostasis - Investigating neurodevelopmental processes and synaptic plasticity, which may have implications in neurodegenerative diseases
Top Products
For researchers investigating CNR1, we recommend two primary antibodies that cater to different experimental needs. The first is the well-cited polyclonal antibody, Anti-Cannabinoid Receptor I antibody (ab23703), which has garnered 137 citations, highlighting its reliability in immunohistochemistry (IHC). This antibody is a trusted choice for those focusing on tissue samples. In addition, we offer the recombinant antibody, Anti-Cannabinoid Receptor I antibody [EPR23934-20] (ab259323), which is suitable for a broader range of applications, including Western blotting (WB), immunocytochemistry (ICC), and flow cytometry (FC). With 14 citations, this recombinant product provides the batch-to-batch consistency that many researchers seek. Together, these antibodies provide versatile options for studying CNR1 effectively.
Abcam Product Citation Summary
The CNR1 antibody ab23703 has been utilised in immunohistochemistry studies specifically focusing on human heart tissue. This suggests a potential role of CNR1 in cardiac biology or pathology.
Abcam Product Citation Table
Function
G-protein coupled receptor for endogenous cannabinoids (eCBs), including N-arachidonoylethanolamide (also called anandamide or AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids, such as delta(9)-tetrahydrocannabinol (THC) (PubMed:15620723, PubMed:27768894, PubMed:27851727). Mediates many cannabinoid-induced effects, acting, among others, on food intake, memory loss, gastrointestinal motility, catalepsy, ambulatory activity, anxiety, chronic pain. Signaling typically involves reduction in cyclic AMP (PubMed:1718258, PubMed:21895628, PubMed:27768894). In the hypothalamus, may have a dual effect on mitochondrial respiration depending upon the agonist dose and possibly upon the cell type. Increases respiration at low doses, while decreases respiration at high doses. At high doses, CNR1 signal transduction involves G-protein alpha-i protein activation and subsequent inhibition of mitochondrial soluble adenylate cyclase, decrease in cyclic AMP concentration, inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system, including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive oxygen species (ROS) formation and mediates cannabinoid-induced increase in SREBF1 and FASN gene expression. In response to cannabinoids, drives the release of orexigenic beta-endorphin, but not that of melanocyte-stimulating hormone alpha/alpha-MSH, from hypothalamic POMC neurons, hence promoting food intake. In the hippocampus, regulates cellular respiration and energy production in response to cannabinoids. Involved in cannabinoid-dependent depolarization-induced suppression of inhibition (DSI), a process in which depolarization of CA1 postsynaptic pyramidal neurons mobilizes eCBs, which retrogradely activate presynaptic CB1 receptors, transiently decreasing GABAergic inhibitory neurotransmission. Also reduces excitatory synaptic transmission (By similarity). In superior cervical ganglions and cerebral vascular smooth muscle cells, inhibits voltage-gated Ca(2+) channels in a constitutive, as well as agonist-dependent manner (PubMed:17895407). In cerebral vascular smooth muscle cells, cannabinoid-induced inhibition of voltage-gated Ca(2+) channels leads to vasodilation and decreased vascular tone (By similarity). Induces leptin production in adipocytes and reduces LRP2-mediated leptin clearance in the kidney, hence participating in hyperleptinemia. In adipose tissue, CNR1 signaling leads to increased expression of SREBF1, ACACA and FASN genes (By similarity). In the liver, activation by endocannabinoids leads to increased de novo lipogenesis and reduced fatty acid catabolism, associated with increased expression of SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de novo cholesterol synthesis and HDL-cholesteryl ether uptake. Peripherally modulates energy metabolism (By similarity). In high carbohydrate diet-induced obesity, may decrease the expression of mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as well as that of selected glucose/ pyruvate metabolic enzymes, hence affecting energy expenditure through mitochondrial metabolism (By similarity). In response to cannabinoid anandamide, elicits a pro-inflammatory response in macrophages, which involves NLRP3 inflammasome activation and IL1B and IL18 secretion (By similarity). In macrophages infiltrating pancreatic islets, this process may participate in the progression of type-2 diabetes and associated loss of pancreatic beta-cells (PubMed:23955712).
Isoform 1
Binds both 2-arachidonoylglycerol (2-AG) and anandamide.
Isoform 2
Only binds 2-arachidonoylglycerol (2-AG) with high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an inverse agonist on isoform 2 in assays measuring GTP binding to membranes.
Isoform 3
Only binds 2-arachidonoylglycerol (2-AG) with high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an inverse agonist on isoform 3 in assays measuring GTP binding to membranes.
Involvement in disease
Obesity
OBESITY
A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.
None
The protein represented in this entry may be involved in disease pathogenesis. May contribute to the development of diet-induced obesity and several obesity-associated features, such as dyslipidemia and liver steatosis, regulating peripheral lipogenesis, energy expenditure and feeding behavior. CNR1 inverse agonists have been shown to reduce body weight and improve metabolic abnormalities in obese subjects, although adverse neuropsychiatric effects, including anxiety, irritability, and depressed mood, halted their therapeutic development (PubMed:18177726). In obese mice, peripherally restricted CNR1 inverse agonists have been shown to normalize metabolic abnormalities, including insulin resistance and fatty liver, and to reverse leptin resistance.
Dysfunction of the endogenous cannabinoid system including CNR1 has been implicated in the pathogenesis of a number of central nervous system disorders, including Huntington disease, Parkinson disease, and Alzheimer disease (PubMed:32549916). In post-mortem brains from Huntington disease patients, a progressive CNR1 loss has been observed in the caudate nucleus, putamen, and substantia nigra pars reticulata, and altered expression and abnormal endocannabinoid levels precede motor symptoms in a disease mouse model (PubMed:10828533, PubMed:19524019, PubMed:8255419). In Parkinson disease, low CNR1 expression in mid-superior frontal gyrus and mid-cingulate cortex has been associated with poor mind, poor executive functioning and poor episode memory, while patients with more severe visuospatial dysfunction showed decreased receptor availability in the precuneus, mid-cingulate, supplementary motor cortex, inferior orbitofrontal gyrus and thalamus (PubMed:31342135). In an animal model for Alzheimer disease, CNR1 heterozygous deletion has been associated with decreased levels of postsynaptic density protein 95 (DLG4/PSD95) and accelerated memory impairment, suggesting synaptic dysfunction and a crucial role for CNR1 in the progression of disease symptoms (PubMed:10828533, PubMed:19524019, PubMed:30096288, PubMed:31342135, PubMed:8255419).
Post-translational modifications
Palmitoylation at Cys-415 is important for recruitment at plasma membrane and lipid rafts and association with G protein alpha subunits.
Sequence Similarities
Belongs to the G-protein coupled receptor 1 family.
Tissue Specificity
Widely expressed, with highest levels in fetal and adult brain. Expression levels of isoform 2 and isoform 3 are much lower than those of isoform 1.
Cellular localization
- Cell membrane
- Multi-pass membrane protein
- Membrane raft
- Mitochondrion outer membrane
- Cell projection
- Axon
- Presynapse
- Unexpectedly, in the mitochondria, the C-terminus is located in the mitochondrial intermembrane space, a compartment topologically considered as extracellular. In canonical seven-transmembrane G-protein coupled receptors, the C-terminus is cytosolic (By similarity). Found on presynaptic axon terminals in some GABAergic neurons in the somatosensory cortex (By similarity).
Alternative names
CNR, CNR1, Cannabinoid receptor 1, CB-R, CB1, CANN6